Somatostatin (SRIF)-like immunoreactivity (SRIF-LI) is widely distributed through the central nervous system as well as being present in D-cells of the pancreatic islets and gut. SRIF and other peptides with a similar widespread tissue distribution have been identified in unicellular organisms and may be ancient in evolutionary terms. Primeval functions of such peptides may have changed according to local tissue needs with increasing complexity of the organism, as may the mode of delivery (neurotransmission, endocrine or paracrine), while their original overall role may have been retained. In the pancreas and gut SRIF-LI responds to ingested food and circulating nutrients and appears to play a role in the regulation of nutrient homeostasis by influencing both nutrient entry and disposition. The hypothalamus influences nutrient homeostasis through modulation of pituitary hormone secretion, appetite regulation and autonomic nervous control over peripheral glucoregulation. SRIF-LI is present in hypothalamic neurones in areas important in these activities and SRIF influences all three aspects of hypothalamic function. This proposal is based on the hypothesis that SRIF in the hypothalamus, like that in the pancreas and gut, responds to nutrient stimuli to mediate hypothalamic influences on metabolic control. In accordance with this hypothesis hypothalamic lesions that affect metabolic control would alter nutrient regulation of hypothalamic SRIF. Conversely, abnormal peripheral nutrient homeostasis would influence hypothalamic function through disturbances of SRIF regulation. Studies in this proposal are designed to examine this hypothesis by identifying nutrient influences on hypothalamic SRIF-LI secretion and then evaluating disturbances of hypothalamic SRIF-LI regulation (biosynthesis, nuclear content, secretion and molecular heterogeneity) resulting from hypothalamic nuclear lesions or diabetes mellitus.